Mapping structural and dynamic divergence across the MBOAT family
Membrane-bound O-acyltransferases (MBOATs) are membrane-embedded enzymes that catalyze acyl chain transfer to a diverse group of substrates, including lipids, small molecules, and proteins. MBOATs share a conserved structural core, despite wide-ranging functional specificity across both prokaryotes...
Gespeichert in:
Veröffentlicht in: | Structure (London) 2024-07, Vol.32 (7), p.1011-1022.e3 |
---|---|
Hauptverfasser: | , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
Zusammenfassung: | Membrane-bound O-acyltransferases (MBOATs) are membrane-embedded enzymes that catalyze acyl chain transfer to a diverse group of substrates, including lipids, small molecules, and proteins. MBOATs share a conserved structural core, despite wide-ranging functional specificity across both prokaryotes and eukaryotes. The structural basis of catalytic specificity, regulation and interactions with the surrounding environment remain uncertain. Here, we combine comparative molecular dynamics (MD) simulations with bioinformatics to assess molecular and interactional divergence across the family. In simulations, MBOATs differentially distort the bilayer depending on their substrate type. Additionally, we identify lipid binding sites surrounding reactant gates in the surrounding membrane. Complementary bioinformatic analyses reveal a conserved role for re-entrant loop-2 in MBOAT fold stabilization and a key hydrogen bond bridging DGAT1 dimerization. Finally, we predict differences in MBOAT solvation and water gating properties. These data are pertinent to the design of MBOAT-specific inhibitors that encompass dynamic information within cellular mimetic environments.
[Display omitted]
•MBOAT subfamilies differentially distort the surrounding bilayer•Conserved residue pairs on re-entrant loop-2 stabilize the MBOAT fold•A conserved hydrogen bond interconnects the DGAT1 dimer•Solvent gating and hydration properties differ across the family
Ansell et al. use molecular dynamics simulations and bioinformatic analyses to compare interactions across the MBOAT family. MBOAT subfamilies differentially interact with themselves, the surrounding membrane, and solvent environments. These data are pertinent to the design of MBOAT-specific inhibitors and family classification. |
---|---|
ISSN: | 0969-2126 1878-4186 1878-4186 |
DOI: | 10.1016/j.str.2024.03.014 |